基于肠道菌群“从脾论治”疾病易感痰湿体质的中医治未病的生物学基础研究

Phlegm-dampness constitution is susceptible of obesity-diabetes-cognitive impairment, and the core element of its formation is dys-splenism. Previously, treating from the spleen with related prescriptions plays an important role in the regulation of phlegm-dampness constitution, and in the prevention and treatment of the development of obesity, diabetes mellitus and cognitive impairment. However, the mechanism is not definite. This project is based on the preliminary research basis, puts forward the scientific hypothesis “gut microbiota is the soil of phlegm-dampness constitution”, “preventive treatment of disease” starts from the improvement of “gut microbiota soil”. We will use the rats with obesity-diabetes-cognitive impairment as models, with 16S rRNA, targeted metabolomics, molecular biology and other methods, to observe the role of pathological gut microbiota in the prevention of diabetes mellitus and its concurrent cognitive impairment. The decoctions as representative prescriptions of treating determination based on the spleen prove gut microbiota and its metabolites, of which the mechanism is to regulate insulin resistance through the gut microbiota metabolites (short chain fatty acids)-gut-brain axis. We hope to explain not only the biological basis of phlegm-dampness (obesity-diabetes-cognitive impairment), but also the key target of “prescription of spleen”. To prevent and delay diabetes and concurrent cognitive dysfunction in early period from gut microbiota soil is the specific manifestation of TCM "preventive treatment of disease" theory and a clinically effective prevention and control strategy.

痰湿体质是肥胖-糖尿病-认知功能障碍的易感体质，脾失健运是其形成的核心要素。既往“从脾论治”方药在调理痰湿体质，控制肥胖预防糖尿病，防治糖尿病认知功能障碍发病中发挥重要作用，但其机制不清。本项目基于前期研究基础，提出“痰湿体质的肠道菌群土壤”的科学假说，“治未病”即从改良“肠道菌群土壤”入手。我们以肥胖-糖尿病-认知功能障碍大鼠为模型，采用16S rRNA、靶向代谢组学及分子生物学等方法，观察病理性肠道菌群对糖尿病及其认知功能障碍的影响，“从脾论治”方药对大鼠肠道菌群及其代谢物的改善，探讨其机制是通过肠道菌群代谢物（短链脂肪酸）-肠-脑轴调控外周和脑胰岛素抵抗实现，阐释痰湿体质（肥胖-糖尿病-认知功能障碍）的生物学机制及“从脾论治”方药作用的关键靶点。从改良肠道菌群土壤揭示早期预防和延缓糖尿病及其认知功能障碍，是中医“治未病”思想“未病先防、既病防变”的具体体现和临床有效的防治策略。

痰湿体质是肥胖-糖尿病-认知功能障碍的易感体质，脾失健运是其形成的核心要素。既往“从脾论治”方药在调理痰湿体质，控制肥胖预防糖尿病，防治糖尿病认知功能障碍发病中发挥重要作用，但其机制不清。本项目基于前期研究基础，提出“痰湿体质的肠道菌群土壤”的科学假说，“治未病”即从改良“肠道菌群土壤”入手。我们完成了研究内容一、肥胖-糖尿病-认知功能障碍大鼠肠道菌群能促进2型糖尿病及其认知功能障碍的发生。二、“从脾论治”方药预防2型糖尿病的发生、延缓糖尿病并发认知功能障碍的药效观察及对大鼠肠道菌群及其代谢物变化的影响。三、“从脾论治”方药通过肠道菌群代谢物（短链脂肪酸）-肠-脑轴调控胰岛素抵抗。取得的主要重要结果和关键数据包括：1.在ZDF大鼠中观察到的变化表明，痰湿体质大鼠对肠道环境稳态的变化缺乏适应能力，痰湿体质“肠道菌群土壤”特征的改变可能导致2型糖尿病和糖尿病认知功能障碍疾病发展过程中微生物-肠-脑轴发生变化，加速糖脂代谢紊乱和认知缺陷的发生。菌群移植作为一种被热点关注和未来可期的治疗手段，可以通过调节疾病早期个体肠道菌群的结构，影响其功能和代谢，从而对疾病进程产生逆转。2.作为“下游”的代谢组学变化有助于解释肥胖-糖尿病-认知功能障碍疾病进程中肠道微生物组学的功能变化，相关潜在生物标志物的发现为肥胖-2型糖尿病-认知功能障碍的前期诊断和“从脾论治”方药的潜在机制提供依据。3.从脾论治是能够控制肥胖、延缓2型糖尿病的发生进程及其并发症糖尿病认知功能障碍的发生与发展的有效策略及方法，并起到未病先防、既病防变的作用。其作用通过调节肠道菌群代谢物（短链脂肪酸）-肠-脑轴调控胰岛素抵抗来实现。通过我们的研究证实了以上的科学假说，阐明了从改良肠道菌群土壤揭示早期预防和延缓糖尿病及其认知功能障碍，是中医“治未病”思想“未病先防、既病防变”的具体体现和临床有效的防治策略。